Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T

Abstract

Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: left ventricle (LV); familial hypertrophic cardiomyopathy (FHC); cardiac troponin T (cTnT); tropomyosin (TM); free energy of ATP hydrolysis (∆G∼ATP); inorganic phosphate (Pi); phosphocreatine (PCr); nontransgenic (NTG); LV developed pressure (DevP); rate pressure product (RPP); myocardial oxygen consumption (MVO2); sarcoplasmic reticular Ca 2+ -ATPase (SERCA).

Sarcomeric Proteins and Familial Hypertrophic Cardiomyopathy: Linking Mutations in Structural Proteins to Complex Cardiovascular Phenotypes

“…Measurements of Ca 2+ sensitive force before and after PKA-dependent stimulation suggested that the observed effects were secondary to the increased Ca 2+ sensitivity of the D175N myofilaments and the expected increase in crossbridge cycling under activating conditions. Lastly, in collaboration with the Ingwall laboratory, measurements of cardiac energetics using 31 P NMR spectroscopy and contractile performance of the intact beating heart revealed both a decrease in the free energy of ATP hydrolysis available to support contractile work and a marked inability to increase contractile performance upon acute inotropic challenge in our previously described cTnT R92Q mice [89]. Taken together, the results from several independent groups support the hypothesis that independent changes in thin filament structure can cause alterations in myofilament activation sufficient to significantly compromise myocellular calcium homeostasis and whole-heart contractile reserve.…”

Insights into the kinetics of Ca2+-regulated contraction and relaxation from myofibril studies

“…The observation that both the kinetics of tension activation and the rate constant k LIN of the initial slow isometric phase of relaxation were markedly increased in the R403Q myofibrils compared to controls is rather striking and shows that the mutation increases g, the rate of dissociation of myosin from actin. Consistent with a wide range of biochemical and nuclear-magnetic-resonance-based studies in both FHC patients and animal models of the disease, this would be expected to greatly increase the overall tension cost in the FHC heart [29,68,72,133]. This myofibril study on an FHC patient represents an important advance both with respect to the conclusions on the observed effects of a specific myosin mutation at the level of the cardiac crossbridge and as a methodology that may provide a unique and more biophysically proximal phenotypic characterisation of FHC.…”

Cardiac troponin T and familial hypertrophic cardiomyopathy: an energetic affair

“…The R92Q missense mutation examined by Javadpour and colleagues in the present study (11) is located in a TnT domain that interacts with It has long been noted that while patients with familial hypertrophic cardiomyopathy due to cardiac troponin T (cTnT) mutations often suffer sudden cardiac death, they do not develop significant ventricular hypertrophy, suggesting that a distinct cellular mechanism apart from alterations in myocardial contractility is responsible. A new study (see the related article beginning on page 768) has revealed that a single missense mutation in cTnT causes a striking disruption to energy metabolism, leading to cardiomyopathy.…”

“…Consistent with these observations, Javadpour et al (11) show that the R92Q mutation, when expressed in the mouse heart (67% replacement of the wild-type protein), decreases the energetic driving force within cardiac myocytes (|∆G ∼ATP | = free energy of ATP hydrolysis) by increasing ATP utilization, most likely because of a mutation-induced boosting of myofibrillar ATPase activity. Very interestingly, all mechanical parameters at the base-line calcium concentration of 2.5 mM were normal, except the maximum rate of left ventricular pressure decay (-dP/dt), which was decreased by 26%, indicative of diastolic dysfunction.…”

“…A critical feature of this study is that measurements were taken in the intact heart, where the impact of small perturbations at the protein level can be summed over a large number of myofibrils (11). The results are important for a number of reasons.…”